The work leading to the invention disclosed herein was generously supported by the National Cancer Institute (CA 18141) and by Career Development Award to Dr. Frank M. Hauser (CA 00487).
The present invention relates to the production (method and object compound thereof), from readily prepared starting materials, of 6-acetyl-4a,5,6,7,8,8a-hexahydro-1(4H)-naphthalenone, a novel compound which is especially useful as a precursor in the synthesis of 9-acetyl-6-hydroxy-4-methoxy-7,8,9,10-tetrahydronaphthacene-5,12-dione--an established late-stage intermediate to the anthracycline antibiotics 11-deoxydaunorubicin and 11-deoxyadriamycin.
The object hexahydronaphthalenone compound can be represented as: ##STR1##
The anthracycline antibiotics 11-deoxydaunorubicin and 11-deoxyadriamycin, 11-deoxy analogs of the therapeutically useful anthracycline antibiotics daunorubicin and adriamycin, were isolated by Arcamone et al., J. Am. Chem. Soc. 1980, 102, 1462, from microorganisms. While these 11-deoxy compounds are somewhat less active as anticancer agents than either daunorubicin or adriamycin, they exhibit significantly less cardiotoxicity, and are potentially important compounds for the treatment of various cancers.
In view of the high cost of producing these antibiotics microbiologically, various attempts to develop effective synthetic routes for their production have been reported. Particular emphasis, for example, has been placed on preparing the aglycone fragment which can be coupled with daunosamine, the amino sugar fragment, to furnish the parent antibiotic. Syntheses of the aglycone have been reported by Sih et al., Tetrahedron Lett. 1980, 21, 3351; Rapoport et al., Tetrahedron Lett. 1980, 21, 4777; Mondon et al., Tetrahedron Lett. 1980, 21, 3351; J. Chem. Soc. Chem. Commun. 1982, 23, 421; Alexander et al., Tetrahedron Lett. 1981, 22, 3711; Rao et al., Tetrahedron Lett. 1982, 23, 775; and Johnson et al., J. Am. Chem. Soc. 1981, 103, 1561.
The reported procedures suffer from a number of disadvantages. Many are lengthy, low-yield sequences which utilize starting materials that are expensive and/or not readily available.
A general object of the present invention, accordingly, is to provide a convenient method for the preparation of 6-acetyl-4a,5,6,7,8,8a-hexahydro-1(4H)-naphthalenone which is a novel precursor compound to 9-acetyl-6-hydroxy-4-methoxy-7,8,9,10-tetrahydronaphthacene-5,12-dione, and in addition, to provide the novel precursor hexahydronaphthalenone compound itself.
Another and related object is to provide such a method which provides a relatively high overall objective-product yield.
Still another object of the invention is to provide a novel method which utilizes commercially available starting materials.
In accordance with a preferred manner of practicing the invention, the proposed method is characterized by conversion, in several convenient steps described in detail below, of 2-(2-hydroxyethyl)bicyclo[2.2.2]oct-5-ene to 6-acetyl-4a,5,6,7,8,8a-hexahydro-1(4H)-naphthalenone.
The method of the invention results in the production of the object hexahydronaphthalenone product in 55% overall yield.
Other objects and advantages of the invention will become apparent as the same is described below in conjunction with examples which specifically illustrate the invention and its utility. In the description which follows, identical compounds are identified by like numbers which are found in the schematic representations and in the description itself.